Keller Sascha, Nickel Joachim, Zhang Jin-Li, Sebald Walter, Mueller Thomas D
Lehrstuhl für Physiologische Chemie II, Theodor-Boveri Institut für Biowissenschaften (Biozentrum), Universität Würzburg, Am Hubland, D-97074 Wuerzburg, Germany.
Nat Struct Mol Biol. 2004 May;11(5):481-8. doi: 10.1038/nsmb756. Epub 2004 Apr 4.
Bone morphogenetic protein-2 (BMP-2) and other members of the TGF-beta superfamily regulate the development, maintenance and regeneration of tissues and organs. Binding epitopes for these extracellular signaling proteins have been defined, but hot spots specifying binding affinity and specificity have so far not been identified. In this study, mutational and structural analyses show that epitopes of BMP-2 and the BRIA receptor form a new type of protein-protein interface. The main chain atoms of Leu 51 and Asp53 of BMP-2 represent a hot spot of binding to BRIA. The BMP-2 variant L51P was deficient in type I receptor binding only, whereas its overall structure and its binding to type II receptors and modulator proteins, such as noggin, were unchanged. Thus, the L51P substitution converts BMP-2 into a receptor-inactive inhibitor of noggin. These results are relevant for other proteins of the TGF-beta superfamily and provide useful clues for structure-based drug design.
骨形态发生蛋白-2（BMP-2）以及转化生长因子-β（TGF-β）超家族的其他成员可调节组织和器官的发育、维持及再生。这些细胞外信号蛋白的结合表位已得到明确，但迄今为止，尚未鉴定出决定结合亲和力和特异性的热点。在本研究中，突变分析和结构分析表明，BMP-2的表位与BRIA受体形成了一种新型的蛋白质-蛋白质界面。BMP-2的亮氨酸51（Leu 51）和天冬氨酸53（Asp53）的主链原子代表了与BRIA结合的一个热点。BMP-2变体L51P仅在与I型受体结合方面存在缺陷，而其整体结构以及与II型受体和调节蛋白（如头蛋白）的结合均未改变。因此，L51P替代将BMP-2转化为一种头蛋白的受体非活性抑制剂。这些结果与TGF-β超家族的其他蛋白相关，并为基于结构的药物设计提供了有用线索。
